The overall objective of this Translational Research Proposal is to synthesize, characterize, and advance an optimized galanin-based analog to IND filing so that a human proof-of-concept clinical trial with a novel first-in-class therapeutic can be conducted in patients with refractory epilepsy. Most of the available antiepileptic drugs (AEDs) exert their activity by modulating voltage- and/or receptor-gated ion channels. Despite treatment with currently available AEDs, approximately 25-40% of patients with refractory partial epilepsy continue to experience uncontrolled seizures, so clearly there is a need for a novel approach. The endogenous neuropeptide galanin and its associated receptors play an important role in the control of seizures and is therefore an attractive therapeutic target. However, developing neuropeptides as therapeutics has been challenging due to their intrinsic lack of metabolic stability and inability to cross the blood-brain-barrier. We have applied a novel technology platform to develop a galanin analog, NAX 5055, that is metabolically stable, maintains low nanomolar affinity for galanin receptors and following systemic administration is effective in an animal seizure model that displays resistance to the majority of first-line AEDs. The Aims outlined in this proposal are designed to optimize the NAX 5055 backbone and to advance one compound to an IND filing as follows: 1) identify one to six optimized galanin receptor 2-preferring analogs that display potent anticonvulsant activity and wide behavioral, cognitive and metabolic safety margins; 2) select at least one IND candidate based on the most favorable pharmacological and ADME profiles; 3) develop a formulation that maintains efficacy in animal models following systemic administration and is suitable for further preclinical and clinical development; 4) and 5) perform all necessary IND-enabling preclinical studies. Successful completion of Aims 1 - 5 will allow the development of a clinical plan and submission of an IND application with the FDA to begin clinical trials of a new, first-in-class neurotherapy for refractory epilepsy.